Sterol-regulatory element-binding protein (SREBP)-2 contributes to polygenic hypercholesterolaemia.

Sterol-regulatory element-binding protein (SREBP)-2 is a key regulator of cholesterol. When cells are deprived of cholesterol, proteolytic cleavage releases the NH(2)-terminal domain of SREBP-2 that binds and activates the promoters of SREBP-2-regulated genes including the genes encoding the low-density lipoprotein (LDL) receptor, 3-hydroxymethyl-3-glutaryl-(HMG-)CoA-synthase, and HMG-CoA-reductase. Thus, SREPB-2 gene activation leads to enhanced cholesterol uptake and biosynthesis. A novel protein polymorphism (SREBP-2-595A/G) discovered in the regulatory domain of human SREBP-2 was investigated regarding its impact on cholesterol homeostasis. In human embryonic kidney (HEK)-293-cells, the cleavage-rate of the SREBP-2-595A-isoform was slightly decreased compared to that of the SREBP-2-595G-isoform. Since cleavage of SREBP-2 activates the LDL receptor-mediated uptake of plasma cholesterol, we hypothesized the LDL receptor-mediated uptake to be decreased in homozygous SREBP-2-595A-carriers and thus, plasma total cholesterol (TC) to be higher than in SREBP-2-595G-carriers. Multiple linear regression analysis of population samples from Switzerland (N=1334) and Israel (N=923) demonstrated a significant positive, gene dose-dependent association of the SREBP-2-595A-isoform with higher plasma TC (P=0.001). This cholesterol-modulating effect was present in hypercholesterolaemic (DeltaTC=1.05 mmol/l, 14.4%; P=0.002; N=477), but absent in normocholesterolaemic subjects (DeltaTC=0.06 mmol/l, 1.4%; P=0.334; N=1780). In summary, a slightly but constantly decreased cleavage-rate of the SREBP-2-595A-isoform compared to that of the SREBP-2-595G-isoform may lead to a reduced transcriptional activation of the LDL receptor-gene weakening the SREBP-mediated compensation mechanisms, and may, therefore, be a critical factor in the development of polygenic hypercholesterolaemia.

Leaf-to-shoot apex movement of symplastic tracer is restricted coincident with flowering in Arabidopsis.

Classical experiments in plant physiology showed that leaves are the source of signals that control the development of flowers from shoot meristems. Additional physiological and genetic experiments have indicated some of the molecules (e.g., gibberellins, cytokinins, and sucrose) that promote flowering in mustards including Arabidopsis. These small hydrophilic molecules are likely to move to the shoot apex symplastically via the phloem and/or via cell-to-cell movement through plasmodesmata. To analyze potential changes in the symplastic trafficking of small molecules during the induction of flowering in Arabidopsis, we measured changes in the flow of symplastic tracers from the leaf to the shoot apex. We previously found that the onset of flowering is coincident with an evident decrease in the leaf-to-shoot trafficking of symplastic tracer molecules; this decrease in trafficking is transitory and resumes when floral development is established. Here we provide detailed analyses of symplastic connectivity during floral induction by monitoring tracer movement under different photoperiodic induction conditions and in a number of genetic backgrounds with altered flowering times. In all cases, the correlation between flowering and the reduction of symplastic tracer movement holds true. The lack of tracer movement during the induction of flowering may represent a change in plasmodesmal selectivity at this time or that a period of reduced symplastic communication is associated with floral induction.